The aging process in the human species leads to the deterioration of higher CNS functions. Age-related changes experienced by cerebral cortex neurons and their synapses are at the heart of these cognitive deficiencies observed in the old age. There is, however, scanty experimental data defining which neocortical neurons and which synapses are most affected structurally or functionally and in which temporal sequence. This project will test the hypothesis that 1) large pyramidal neurons are more sensitive than non-pyramidal cortical neurons to the aging process and that 2) an imbalance between excitatory and inhibitory influences upon pyramidal neurons might exist in the neocortex of cognitively impaired aged individuals. To test the above hypotheses a multidisciplinary team will apply a combination of behavioral, physiological (single cell electrophysiological, patch clamp) and morphological (light and electron microscopy immunocytochemistry of intracellularly labeled neurons) studies to define which particular cerebral cortex neurons are most affected with aging, what is their synaptic pattern and whether an imbalance between excitatory and inhibitory synaptic discharges occur in memory impaired aged animals when compared with aged non-impaired animals. This research should reveal which neuronal and transmitter-specific synaptic systems are more vulnerable to the aging process, thus providing valuable clues for their protection and/or corrective pharmacological treatments.